Joubert syndrome

Joubert syndrome is disorder of brain development that may affect many parts of the body. Joubert syndrome is characterized by the absence or underdevelopment of the cerebellar vermis (a part of the brain that controls balance and coordination) and a malformed brain stem (connection between the brain and spinal cord). Together, these cause the characteristic appearance of a molar tooth sign on MRI (see Figure 4 below). The signs and symptoms of Joubert syndrome vary among affected individuals, even among members of the same family, but commonly include weak muscle tone (hypotonia), abnormal breathing patterns, abnormal eye movements, difficulty coordinating movements (ataxia), distinctive facial features and intellectual disability. Various other abnormalities may also be present.

Joubert syndrome is one of a growing group of disorders called “ciliopathies” caused by dysfunction of a part of the cell called the cilium. The cilium functions as an antenna for many cell types, allowing cells to communicate with each other and sense their environment during the development and function of many organs. In fact, cilia are required to sense light in the eye, odors in the nose and fluid flow in the kidneys and liver. Disruption of cilium function likely explains the incidence of eye, kidney and liver problems in individuals with Joubert syndrome.

The hallmark feature of Joubert syndrome is a combination of brain abnormalities that together are known as the molar tooth sign, which can be seen on brain imaging studies such as magnetic resonance imaging (MRI) (see Figure 4 below). This sign results from the abnormal development of structures near the back of the brain, including the cerebellar vermis and the brainstem. The molar tooth sign got its name because the characteristic brain abnormalities resemble the cross-section of a molar tooth when seen on an MRI.

Most infants with Joubert syndrome have low muscle tone (hypotonia) in infancy, which contributes to difficulty coordinating movements (ataxia) in early childhood. Other characteristic features of the condition include episodes of unusually fast (hyperpnea) or slow (apnea) breathing in infancy, and abnormal eye movements (ocular motor apraxia). Most affected individuals have delayed development and intellectual disability, which can range from mild to severe. Distinctive facial features can also occur in Joubert syndrome; these include a broad forehead, arched eyebrows, droopy eyelids (ptosis), widely spaced eyes (hypertelorism), low-set ears, and a triangle-shaped mouth.

Joubert syndrome can include a broad range of additional signs and symptoms. The condition is sometimes associated with other eye abnormalities (such as retinal dystrophy, which can cause vision loss, and coloboma, which is a gap or split in a structure of the eye), kidney disease (including polycystic kidney disease and nephronophthisis), liver disease, skeletal abnormalities (such as the presence of extra fingers and toes), or hormone (endocrine) problems. A combination of the characteristic features of Joubert syndrome and one or more of these additional signs and symptoms once characterized several separate disorders. Together, those disorders were referred to as Joubert syndrome and related disorders. Now, however, any instances that involve the molar tooth sign, including those with these additional signs and symptoms, are usually considered Joubert syndrome.

Joubert syndrome is estimated to affect between 1 in 80,000 and 1 in 100,000 newborns ¹. However, this estimate may be too low because Joubert syndrome has such a large range of possible features and is likely underdiagnosed. Particular genetic mutations that cause this condition are more common in certain ethnic groups, such as Ashkenazi Jewish, French-Canadian, and Hutterite populations.

Joubert syndrome may be caused by mutations in any of many genes. Inheritance is usually autosomal recessive, but rarely it may be X-linked recessive.

The treatment for Joubert syndrome is symptomatic and supportive. Developmental delays are usually treated with physical therapy, occupational therapy, speech therapy and infant stimulation. Individuals with Joubert syndrome should be evaluated by appropriate specialists including nephrologists, ophthalmologists, geneticists and neurologists. Annual screening is recommended for liver, kidney and retinal abnormalities.

Genetic counseling is recommended for individuals with Joubert syndrome and their families.

Figure 1. Joubert syndrome

Footnote: Clinical features in Joubert syndrome. (A) Facial features in a girl with Joubert syndrome (COACH syndrome) at age 27 months showing broad forehead, arched eyebrows, strabismus, eyelid ptosis (on right eye), and open mouth configuration indicating reduced facial tone. (B) Oral findings in a child with oral-facial-digital syndrome-like features of Joubert syndrome showing midline upper lip cleft (arrowhead), midline groove of tongue, and bumps of the lower alveolar ridge (arrow). (C) Left hand of an infant with Joubert syndrome and postaxial polydactyly (arrow). (D) Left foot of an infant with Joubert syndrome and preaxial polydactyly of the hallux. (E) View from above of an infant with a small occipital encephalocele with protrusion of the occiput of the skull (arrow)

[Source ² ]

Is Joubert syndrome more common in people of French Canadian descent?

Yes. There is a relatively high prevalence of Joubert syndrome and related disorders in the French Canadian population, with several founder effects noted ³. A founder effect is the effect on a gene pool that occurs when a new population is formed (founded) by a small number of individuals from a larger population, with limited genetic variation. Founder effects are typically associated with an increase in the frequency of a specific autosomal recessive allele (version of a gene) ⁴.

The family first described by Joubert et al in 1969 has been traced to a founder who immigrated to Quebec from France in the 1600s. However, it reportedly appears that there are other founder groups in the French Canadian population ³. Scientists are not aware of reports stating the prevalence or carrier frequency of Joubert syndrome in this population.

The exact incidence or prevalence of Joubert syndrome and related disorders in the general population has not been determined, but many authors use a range between 1 in 80,000 and 1 in 100,000. This may be an underestimate ³.

Is there a connection between Joubert syndrome and autism?

There is a connection, but it remains somewhat unclear. Autism is a relatively common condition, occurring in 1 in 500 children, and is more likely in boys with a 4:1 male:female ratio. There are likely many different causes for this increasingly common diagnosis. Features of classical autism include poor eye contact and limited communication skills as well as repetitive or self-stimulatory behaviors. Autism has been reported in a number of children with Joubert syndrome in several publications. However, more recent surveys suggest that these behavioral disturbances do not represent classic autism, but are more likely to be related to the underlying cerebellar disorder, eye movement problems, and associated developmental disabilities ⁵.

Can steroid use increase the chance to have a child with Joubert syndrome?

No. A person with a history of steroid use does not have a higher chance to have a child with Joubert syndrome. Joubert syndrome is a genetic condition caused by changes (mutations) in genes that can be passed from parent to child. These mutations are present from birth and are not acquired during a person’s lifetime.

Joubert syndrome causes

Joubert syndrome can be caused by mutations in more than 30 genes. The proteins produced from these genes are known or suspected to play roles in cell structures called primary cilia. Primary cilia are microscopic, finger-like projections that stick out from the surface of cells and are involved in sensing the physical environment and in chemical signaling. Primary cilia are important for the structure and function of many types of cells, including brain cells (neurons) and certain cells in the kidneys and liver. Primary cilia are also necessary for the perception of sensory input, which is interpreted by the brain for sight, hearing, and smell.

Mutations in the genes associated with Joubert syndrome lead to problems with the structure and function of primary cilia. Defects in these cell structures can disrupt important chemical signaling pathways during development. Although researchers believe that defective primary cilia are responsible for most of the features of these disorders, it is not completely understood how they lead to specific developmental abnormalities.

Mutations in the genes known to be associated with Joubert syndrome account for about 60 to 90 percent of all cases of this condition. In the remaining cases, the genetic cause is unknown.

Ten genes have been identified that cause Joubert syndrome. A mutation in the AHI1 (JBTS3) gene is responsible for this condition in approximately 11% of families. Affected individuals with this gene mutation often have impaired vision due to retinal dystrophy. A mutation in the NPHP1 (JBTS4) gene causes approximately 1-2% of Joubert syndrome. Affected individuals with this gene mutation often develop a progressive kidney disease called nephronophthisis. A mutation in the CEP290 (JBTS5) gene causes about 4-10% of Joubert syndrome. Mutations in the TMEM67 (JBTS6), JBTS1, JBTS2, JBTS7, JBTS8 and JBTS9 genes are also associated with Joubert syndrome. Other genes responsible for Joubert syndrome are currently unknown.

Joubert syndrome inheritance pattern

Joubert syndrome typically has an autosomal recessive pattern of inheritance, which means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell (see Figure 2). The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they usually do not show signs and symptoms of the condition. Affected people inherit one mutated copy of the gene from each parent, who is referred to as a carrier. Carriers of an autosomal recessive condition typically do not have any signs or symptoms (they are unaffected). When 2 carriers of an autosomal recessive condition have children, each child has a:

• 25% chance to be affected
• 50% chance to be an unaffected carrier like each parent
• 25% chance to be unaffected and not a carrier.

In rare cases, when Joubert syndrome is caused by mutations in the OFD1 gene on the X chromosome, it is inherited in an X-linked recessive manner ⁶. X-linked recessive conditions usually occur in males, who only have one X chromosome (and one Y chromosome) (see Figure 3). Females have two X chromosomes, so if they have a mutation on one X chromosome, they still have a working copy of the gene on their other X chromosome and are typically unaffected. While females can have an X-linked recessive condition, it is very rare. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

If a mother is a carrier of an X-linked recessive condition and the father is not, the risk to children depends on each child’s sex.

• Each male child has a 50% chance to be unaffected, and a 50% chance to be affected
• Each daughter has a 50% chance to be unaffected, and a 50% chance to be an unaffected carrier

If a father has the X-linked recessive condition and the mother is not a carrier, all sons will be unaffected, and all daughters will be unaffected carriers.

Figure 2. Joubert syndrome autosomal recessive inheritance pattern

Figure 3. Joubert syndrome X-linked recessive inheritance pattern

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://www.abgc.net/about-genetic-counseling/find-a-certified-counselor/) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx) has a searchable database of medical genetics clinic services in the United States.

Should I have carrier testing if my male partner has a child with Joubert syndrome?

Joubert syndrome is predominantly inherited in an autosomal recessive manner, in which case both parents must be carriers to have an affected child. In rare cases, Joubert syndrome is inherited in an X-linked recessive manner ³.

• If a male child has autosomal recessive Joubert syndrome, it is assumed his father is a carrier. To have another affected child with a different partner, the partner must also be a carrier of autosomal recessive Joubert syndrome. Many genes can be responsible for Joubert syndrome (some of which are unknown), and digenic inheritance is possible ³. This means that children may be at risk if one parent carries a mutation in one responsible gene, and the other parent carries a mutation in a different responsible gene.
• If a male child has X-linked recessive Joubert syndrome, the most likely reason is that his mother is a carrier of X-linked Joubert syndrome, and the father is not a carrier. Males cannot be “carriers” of X-linked recessive conditions; if they have a mutation in the responsible X-linked gene, they will be affected.

Because the genetics of Joubert syndrome can be complex, people with questions about carrier testing are strongly encouraged to speak with a genetic counselor or other genetics professional. Whether to have genetic testing is a personal decision. A genetic counselor can provide more detailed information about the genetic risks to specific family members. They also discuss the risks, benefits, and limitations of genetic testing, and can facilitate the testing process for people who decide to have testing.

Joubert syndrome symptoms

Many of the clinical symptoms of Joubert syndrome are apparent in infancy and most affected children have delays in gross motor milestones. Most infants with Joubert syndrome have weak muscle tone (hypotonia), which evolves into difficulty coordinating movements (ataxia) in early childhood. Affected children may have episodes of unusually fast or slow breathing (hyperpnea), which tends to occur shortly after birth. This may intensify with emotional stress, but progressively improves with age and usually disappears around 6 months of age ⁷.

Abnormal eye movements are also common. Oculomotor apraxia occurs frequently and causes difficulty moving the eyes from side to side. People with oculomotor apraxia have to turn their heads to see things in their peripheral vision ⁷.

Developmental abilities, in particular language and motor skills, are delayed with variable severity. Mild to severe intellectual disability is common, but some people with Joubert syndrome have normal intellectual abilities ⁷.

Distinctive facial features are also characteristic. These include a broad forehead, arched eyebrows, droopy eyelids (ptosis), widely spaced eyes, low-set ears, and a triangular-shaped mouth ¹.

Joubert syndrome can cause a wide range of additional signs and symptoms. Joubert syndrome is sometimes associated with other eye abnormalities (such as retinal dystrophy, which can cause vision loss), abnormal development of the retina, abnormality in the iris (coloboma), abnormal eye movements (nystagmus), crossed eyes (strabismus), and drooping eyelids (ptosis); kidney disease; liver disease; skeletal abnormalities (such as extra fingers and toes [polydactyly]); a gap in the skull with protrusion of the membranes that cover the brain (encephalocele) and hormone (endocrine) problems. When the characteristic features of Joubert syndrome occur with one or more of these additional features, researchers refer to the condition as “Joubert syndrome and related disorders (JSRD)” ¹ or as a subtype of Joubert syndrome ⁷.

Joubert syndrome is characterized by a specific finding on an MRI called a “molar tooth sign” in which the cerebellar vermis of the brain is absent or underdeveloped and the brain stem is abnormal (see Figure 4 below).

Joubert syndrome diagnosis

The diagnosis of Joubert syndrome is based on the presence of characteristic clinical features as well as the MRI finding of the molar tooth sign ³.

The diagnosis of “classic” or “pure” Joubert syndrome is based on the presence of the following three primary criteria:

• the molar tooth sign on MRI (see Figure 4)
• hypotonia (weak muscle tone) in infancy with later development of ataxia
• developmental delays / intellectual disability

Additional features often identified in people with Joubert syndrome include an abnormal breathing pattern (alternating tachypnea and/or apnea) and abnormal eye movements.

The term “Joubert syndrome and related disorders” refers to those with Joubert syndrome who have additional findings such as retinal dystrophy, renal (kidney) disease, ocular colobomas, occipital encephalocele (protruding tissue at the back of the skull), fibrosis of the liver, polydactyly, and/or other abnormalities. A significant proportion of people diagnosed with classic Joubert syndrome in infancy or early childhood will eventually have additional findings that represent Joubert syndrome and related disorders ³.

While mutations in many genes are known to be associated with Joubert syndrome, they are only identified in about 50% of affected people who have genetic testing. Therefore, genetic testing is not required for a diagnosis of Joubert syndrome or Joubert syndrome and related disorders ³.

Figure 4. Joubert syndrome molar tooth sign

Footnote: Molar tooth sign in Joubert syndrome. Axial MRI image through the cerebellum and brain stem of a child with Joubert syndrome. Arrows indicate the three key components of the molar tooth sign.

Joubert syndrome treatment

To establish the extent of disease in an individual diagnosed with Joubert syndrome, the following baseline evaluations to identify the extent of disease in affected infants/children are recommended ⁸. Recommendations were developed by a consensus panel and are outlined on the Joubert Syndrome and Related Disorders Foundation website (https://jsrdf.org).

• Examination of high-quality MRI scan to assess for cerebral malformations, neuronal migration disorders, or cephaloceles that could portend a poorer prognosis or seizures, if not done at the time of diagnosis
• A baseline neurologic evaluation with particular attention to tone, respiratory pattern (tachypnea and apnea), eye movements, development, and cerebellar function
• Sleep history with polysomnogram as baseline evaluation and particularly if symptomatic apnea is present
• Assessment of oromotor function by a speech therapist and/or by fluoroscopic swallowing studies
• Developmental assessment with age-appropriate tools
• Evaluation by a pediatric ophthalmologist via dilated eye examination for colobomas and retinal changes, as well as strabismus and ptosis, with consideration of specialized testing such as visual-evoked potentials, electroretinogram, and ocular motility testing
• Abdominal ultrasound examination to evaluate for hepatic fibrosis or renal cysts and/or findings consistent with nephronophthisis (e.g., loss of corticomedullary differentiation)
• Tests of renal function, including blood pressure, blood urea nitrogen (BUN), serum creatinine concentration, complete blood count (CBC), and urinalysis from first-morning void for specific gravity to test concentrating ability (if feasible)
• Liver function tests including serum concentrations of transaminases, albumin, bilirubin, and prothrombin time
• For males with micropenis or any child with signs of growth hormone deficiency, endocrine evaluation for other pituitary abnormalities
• Skeletal survey and/or limb radiographs if there is suspicion of a skeletal dysplasia such as short-rib polydactyly or Jeune asphyxiating thoracic dystrophy
• Consultation with a clinical geneticist to document family history, to evaluate growth and head size, and to evaluate for other anomalies including polydactyly, dysmorphic facial features, tongue tumors/lobulations, and micropenis
• Siblings or relatives who have clinical features similar to those of an individual with Joubert syndrome warrant genetic consultation. If the pathogenic variant(s) have been identified in a proband, testing symptomatic relatives for these pathogenic variants is appropriate.

Treatment of manifestations

Respiratory

• Infants and children with abnormal breathing patterns should be considered for apnea monitoring if the abnormality is severe. Supportive therapy may include stimulatory medications such as caffeine or supplementary oxygen, particularly in the newborn period.
• Anesthetic management during surgical procedures for infants with significant respiratory disturbance may be accomplished in some cases by the use of:
  • Regional anesthesia without opioids to avoid exacerbation of apneic episodes ⁹;
  • Alpha-2 agonists such as clonidine or dexmedetomidine to avoid respiratory depression and other complications of opioids while achieving motion-free images ¹⁰.
• In rare cases, mechanical support and/or tracheostomy may be considered in a child with severe respiratory dysfunction.
  Aggressive treatment of middle ear infections is indicated to avoid conductive hearing loss.

Hypotonia and therapeutic interventions

• Appropriate management and therapy of oromotor dysfunction by a speech therapist
• Nasogastric feeding tubes or gastrostomy tube placement for feeding in children with severe dysphagia
• Occupational, physical, and speech therapy through early intervention programs
• Individualized educational assessment and support for school-aged children to maximize school performance
• Periodic neuropsychologic and developmental testing at appropriate ages

Other central nervous system malformations

• Neurosurgical consultation is indicated for those with evidence of hydrocephalus (rapidly increasing head circumference and/or bulging fontanelle). Note: When hydrocephalus occurs in JS, it rarely requires shunting.
• Posterior fossa cysts and fluid collections rarely require intervention.
• Encephalocele may require primary surgical closure.
• Seizures should be evaluated and treated by a neurologist using standard antiepileptic drugs.
• A variety of psychotropic medications have been used to treat the behavioral complications in Joubert syndrome; no single medication has been uniformly effective for all children.

Eye problems

• Surgery as needed for symptomatic ptosis, strabismus, or amblyopia
• Corrective lenses for refractive errors
• Possible vision therapies for oculomotor apraxia, although specific studies are lacking in this disorder
• Interventions for the visually impaired when congenital blindness or progressive retinal dystrophy are present

Renal disease

• Consultation with a nephrologist is indicated.
• End-stage renal disease (ESRD) resulting from nephronophthisis frequently requires dialysis and/or kidney transplantation during the teenage years or later.
• Hypertension, anemia, and other complications of ESRD require specific treatment.

Hepatic fibrosis

• Consultation with a gastroenterologist is indicated.
• Liver failure and/or fibrosis should be managed by a gastroenterologist with arrangements for surgical intervention such as portal shunting for esophageal varices and portal hypertension, as appropriate.
• Some individuals have needed orthotopic liver transplantation.

Skeletal

• Surgical treatment for polydactyly
• Appropriate medical management by an orthopedic specialist for scoliosis

Other

• Orofacial clefting is treated by standard surgical interventions.
• Tongue tumors that impair normal swallowing or cause respiratory obstruction may require surgical resection.
• Symptoms of obstructive sleep apnea and/or tongue hypertrophy in older individuals may require evaluation with a polysomnogram and/or by an otolaryngologist for consideration of adenoidectomy, tonsillectomy, or surgical tongue reduction. Some children have used Bilevel Positive Airway Pressure (BiPAP) or continuous positive airway pressure/power (CPAP) at night.
• Consultation with an endocrinologist for menstrual irregularities and for pituitary hormone deficiency (with hormone replacement as indicated) is appropriate.
• Obesity should be managed with appropriate measures, including diet, exercise, and behavioral therapies
• Congenital heart defects and situs abnormalities should be treated by conventional therapies.
• Surgical correction of Hirschsprung disease (if present) is indicated.

Prevention of secondary complications

Antibiotic prophylaxis for surgical and dental procedures is indicated for individuals with structural cardiac anomalies.

Surveillance

Because no uniformly reliable distinguishing characteristics allow prediction of the complications that may develop in an infant or young child with Joubert syndrome, a number of annual evaluations are recommended:

• Pediatric and neurologic evaluation and monitoring of growth, sexual maturation, breathing (including apnea symptoms), and motor function
• Neuropsychological and developmental evaluation and testing, as appropriate
• Ophthalmologic evaluation for visual acuity, tracking ability, and development of retinal dystrophy
• Abdominal ultrasound examination for evaluation of possible liver and kidney abnormalities
• Liver function tests
• Evaluation of renal function: measurement of blood pressure, serum concentrations of BUN and creatinine, CBC, and assessment of first-morning void urinalysis

Agents and circumstances to avoid

Individuals with renal impairment should avoid nephrotoxic medications such as nonsteroidal anti-inflammatory drugs.

Individuals with liver impairment should avoid hepatotoxic medications.

Joubert syndrome prognosis

The prognosis for infants with Joubert syndrome depends on whether or not the cerebellar vermis is partially developed or entirely absent, as well as on the extent and severity of other organ involvement, such as the kidneys and liver. Some children have a mild form of the disorder, with minimal motor disability and good mental development, while others may have severe motor disability, moderate impaired mental development, and multi-organ impairments. Some patients may have a shortened lifespan due to complications of the disease, including kidney or liver abnormalities.

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